[11β,16α(R)]-16,17-[(cyclohexylmethylene)bis(oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy) pregna-1,4-diene-3,20-dione also known as ciclesonide is a synthetic corticosteroid and is used to decrease inflammation in the lungs. It was first disclosed in DE4129535 and U.S. Pat. No. 5,482,934.
WO9524416 describes a process for the epimer enrichment of pregna-1,4-diene-3,20-dione 16,17 acetal derivatives by silylation.
U.S. Pat. No. 6,787,533 discloses R-epimer enrichment of 16,17-acetal derivatives of 21-acyloxy pregna-1,4-diene-11β,16α,17α-triol-3,20-dione derivatives.
In all the processes disclosed in the prior art, ciclesonide or its intermediates are subjected to repeated crystallisation for epimer enrichment which leads to loss in yield and makes the processes uneconomical for industrial scale up. In one aspect, the present invention is an attempt to provide a new process for the preparation of [11β,16α(R)]-16,17-[(cyclohexylmethylene)bis (oxy)]-11-hydroxy-21-(2-methyl-1-oxopropoxy)-pregna-1,4-diene-3,20-dione.
In the processes of the prior art, ciclesonide is crystallized using a mixture of water and a water miscible solvent. The product thus obtained is in a crystalline form and has an XRD pattern as shown in FIG. 2 and is hereinafter referred to as Form A.
Various crystal modifications of a drug (often referred to as polymorphs) may have substantial differences in physical properties such as particle size hardness. Furthermore, these seemingly-small changes in crystal structure can have a substantially large effect on certain pharmaceutically important properties like dissolution, bioavailability etc. Crystal modifications also include various solvates, hydrates of the drug. Certain drugs have the tendency to form solvates and hydrates.
The existence of a crystal modification of any given compound, which includes solvates and hydrates, cannot be predicted, and there is no standard thumb rule process for preparing a previously unknown crystal modification of a known compound. Even after a crystal modification has been identified, there is no possibility of predicting whether any additional modifications will ever be discovered.
As a result, it would be a landmark contribution in the filed of crystal modification to provide a new crystalline form of ciclesonide, and methods of preparation, pharmaceutical formulations, and methods of use thereof. Also there is further scope and need for an improved process which provides ciclesonide in good yield and purity.
The present invention provides improved processes for the synthesis of ciclesonide which result in ciclesonide having high purity and yield. The present invention further provides a new crystal modification of ciclesonide herein after referred to as Form C and a process for the preparation of Form C.